tbuckley/cabot-search huggingface dataset:
Abstract IA23: Molecular landscapes of hepatocellular carcinoma and cholangiocarcinoma
Authors: Xin Wei Wang
Journal: Clinical Cancer Research (2022)

Abstract Liver cancer is among the top five deadliest cancers in the world, especially in Southeast Asia and Sub-Saharan Africa, and its incidence rates continue to increase in recent decades. Despite considerable efforts towards the development of new prevention, diagnosis and treatment strategies, the improvement of cancer survival is modest. Defined as the unique genotypic and phenotypic differences of cancer cells within a single tumor (intra-tumor) or amongst different patients (inter-tumor), tumor heterogeneity has consistently been linked to worse clinical outcomes in liver cancer. Primary liver cancer mainly consists of two clinical types, i.e., hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), each of which could be further divided into several clinical and molecular subtypes. Chronic liver diseases due to viral hepatitis, alcohol consumption, chemical carcinogens, or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, are major global health burdens that increase the risk of HCC while parasitic infections may be linked to CCA. It is unclear how complex etiological factors determine tumor subtypes and whether common features may be shared among HCC and CCA. Given the presence of so many clinical and molecular variables, it is imperative to develop well-defined cohorts that include diverse etiologies, race/ethnicities, sex and age, which provides an unbiased platform by minimizing confounding factors to study liver cancer types. Accordingly, we have established several national and international collaborative projects, including the NCI-CLARITY study, the NCI-UMD cohort study, the NCI-Mongolian cohort study, and the TIGER-LC (Thailand) consortium. We have applied molecular-based technologies such as genomics, transcriptomics, metabolomics and microbiomics, including single-cell omics to comprehensively analyze biopsies from diverse populations, in order to better characterize heterogeneity among and within patients, to further define tumor molecular subtypes with unique tumor biology and to understand tumor evolution in response to treatment. These studies have led to the discovery of new cell types and drivers in HCC and CCA, potential new mechanisms of therapy resistance and tumor progression, and new insights into the evolutionary patterns of liver cancer. Our past and future ability to translate our research findings towards patient management through the identification of molecular-based knowledge for understanding of liver cancer pathophysiology with the application of early detection and treatment of liver cancer may have a considerable impact on clinical practice and public health. Citation Format: Xin Wei Wang. Molecular landscapes of hepatocellular carcinoma and cholangiocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA23.
Abstract IA14: Lessons learned from phase III trials in HCC: OS, PFS and ORR
Authors: Andrew X. Zhu
Journal: Clinical Cancer Research (2022)

Abstract Through well conducted phase III trials, recent development of molecularly targeted agents, immune checkpoint inhibitors, and combination strategies in advanced hepatocellular carcinoma (HCC) has significantly improved the treatment outcome in this disease. The median overall survival (OS) for patients receiving the new standard treatment, atezolizumab plus bevacizumab, has approached to 20 months in IMbrave150 trial. While OS remains the gold standard and main endpoint for phase III trials in advanced HCC, there is an increasing need to define surrogate endpoints including progression free survival (PFS) and overall response rate (ORR) that can reliably predict the survival benefits. The author will discuss the rationale and current status of using PFS and ORR as surrogate endpoints in HCC, and the strengths and limitations of PFS and ORR as surrogate endpoints to predict survival. Citation Format: Andrew X. Zhu. Lessons learned from phase III trials in HCC: OS, PFS and ORR [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA14.
HIV-1 Protease Inhibitors
Authors: Steven G. Deeks
Journal: JAMA (1997)

<h3>Objective.</h3> —The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (Pis). The 4 Pls available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented. <h3>Data Sources.</h3> —A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996. <h3>Study Selection and Data Extraction.</h3> —Criteria used to select studies include their relevance to Pls, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care. <h3>Data Synthesis.</h3> —Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4<sup>+</sup>lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to Pls occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs. <h3>Conclusions.</h3> —The Pls have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.
Abstract IA25: Clinical trials and molecular therapies in iCCA
Authors: Juan W. Valle
Journal: Clinical Cancer Research (2022)

Abstract Cisplatin and gemcitabine (CisGem) has been the stadard of care for patients presenting with advanced iCCA for over a decade. Intensified (triplet) chemotherapy remains investigational except in Japan, where the CisGem and S1 is an option. Robust data has shown that 5FU-based, second-line, combination chemotherapy has modest activity in a molecularly-unselected population. An improved understanding of the biology underpinning iCCA has led to the identification of molecular alterations linked to targeted therapies. The most prominent alterations are mutations in IDH1 and FGFR2 fusions; both of these are addressed later in the session. This presentation will highlight other selected subgroups, including patients whose tumours are harbouring BRAF-V600E mutations, HER2 amplification/over-expression, and NTRK fusions as examples, although additional groups continue to emerge. Cholangiocarcinoma is recognised to have an underlying immune predisposition, in selected cases. Harnessing the immune response has previously provided limited signals of efficacy. However, the TOPAZ-1 study, a randomised phase III study has recently shown an incremental survival benefit in patients with biliary tract cancer with the addition of durvalumab to CisGem chemotherapy, including intrahepatic cholangiocarcinoma. No predictive factors are known to enrich for patients most likely to benefit from immunotherapy to date. Additional analysis of patient subgroups in TOPAZ-1 as well as the results of the KEYNOTE-966 phase III study (CisGem +/- pembrolizumab) are eagerly awaited. Citation Format: Juan W. Valle. Clinical trials and molecular therapies in iCCA [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA25.
Abstract IA09: Role of liquid biopsy in early detection and assessment of response in hepatocellular carcinoma
Authors: Augusto Villanueva-Rodriguez
Journal: Clinical Cancer Research (2022)

Abstract Early hepatocellular carcinoma detection is suboptimal with less than 25% of eligible patients enrolled in surveillance. In addition, recommended tools (biannual abdominal ultrasound with or without AFP) have poor sensitivity (63% for early-stage tumors). This has prompted the development of liquid biopsy approaches to improve performance and increase implementation. Methylation analysis of circulating tumor DNA and RNA sequencing in extracellular vesicles have shown promising performance in case control studies. This technology has also been applied to identify predictor biomarkers of response to systemic therapies. With 9 agents approved and without a clear strategy on how to select patients for therapies, the need to develop minimally-invasive biomarkers in this space cannot be overemphasized. Citation Format: Augusto Villanueva-Rodriguez. Role of liquid biopsy in early detection and assessment of response in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA09.
Abstract IA03: Polyploidy, DNA damage response driver or gatekeeper of chronic liver diseases
Authors: Chantal Desdouets
Journal: Clinical Cancer Research (2022)

Abstract Polyploidy, also known as whole-genome amplification, is a condition in which the organism has more than the two basic sets of chromosomes. Polyploidy frequently arises during tissue development and repair, and in age-associated diseases, such as cancer. Its consequences are diverse and clearly different between systems. The liver is a particularly fascinating organ in that it can adapt its ploidy to the physiological and pathological context. In human liver parenchyma, polyploidy is mainly cellular (binuclear hepatocytes) with no specific zonation across the liver lobule. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumors. Remarkably, nuclear ploidy is specifically amplified in HCC tumors. In fact, nuclear ploidy is amplified in HCCs harboring a low degree of differentiation and TP53 mutations. Highly polyploid tumors are associated with a poor prognosis. Hepatocytes increase their ploidy also during the proliferative stress that underlies various liver disease conditions. Recently, we investigated mechanisms underlying activation of the DNA damage response during Non-alcoholic Steatotic Liver Disease. We demonstrated that proliferating mouse NAFLD hepatocytes harbor replication stress with an alteration of the replication fork’s speed and activation of ATR pathway which is sufficient to cause DNA breaks. Nucleotide pool imbalance occurring during NAFLD is the key driver of replication stress. Remarkably, DNA lesions drive cGAS/STING pathway activation, a major component of cells’ intrinsic immune response. The translational significance of this study was reiterated by showing that lipid overload in proliferating HepaRG was sufficient to induce replication stress and nucleotide pool imbalance. Moreover, livers from NAFLD human patients displayed nucleotide pathways deregulation and cGAS/STING genes alteration. Altogether, our findings shed new light on the mechanisms by which damaged NAFLD hepatocytes might promote disease progression. Citation Format: Chantal Desdouets. Polyploidy, DNA damage response driver or gatekeeper of chronic liver diseases [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA03.
Abstract PO002: Pretreatment immune cell composition and checkpoint ligand expression define the response to immunotherapy in advanced HCC: a study using single-cell sequencing
Authors: Sarah Cappuyns, Gino Philips, Vincent Vandecaveye, Chris Verslype, Eric Van Cutsem, Diether Lambrechts, Jeroen Derkervel
Journal: Clinical Cancer Research (2022)

Abstract The novel combination of atezolizumab/bevacizumab has demonstrated unprecedented response rates in a subgroup of advanced hepatocellular carcinoma (aHCC) patients. In order to understand why only a subset of aHCC patients respond to immunotherapy targeting the PD-1/PD-L1 axis, we subjected pre-treatment tissue biopsies from 31 aHCC patients, with mainly non-viral etiologies, to simultaneous single-cell transcriptome (scRNAseq) and T-cell receptor (scTCRseq) sequencing, providing an integrative view of the tumor-microenvironment of aHCC (n=91 169 cells). The therapeutic targets, PD-1 and PD-L1 are expressed in tumor-infiltrating T-cells versus myeloid cells and tumor cells, respectively. Myeloid cells in tumors responding to immunotherapy (according to mRECIST) express significantly higher levels of PD-L1 (p=0.014) compared to non-responders and this is driven by pro-inflammatory PD-L1 expressing CXCL10+ macrophages, involved in T-cell recruitment. In contrast, non-responding tumors are infiltrated by immature CX3CR1+ macrophages and CCR2+ ‘monocyte-like’ macrophages (p=0.009 and p=0.01, respectively). Interestingly, the composition of tumor-infiltrating T-cells did not differ significantly between patient groups. However, responding tumors were characterized by a more clonal baseline T-cell receptor repertoire (p=0.007). Single-cell T-cell receptor sequencing revealed that this clonality was present in activated, effector T-cells, while non-responders had a higher proportion of non-clonal T-cells (p=0.01) concentrated within naïve and memory-like T-cell phenotypes. In conclusion, this is the first and largest aHCC cohort to correlate single-cell sequencing data with clinical outcomes. Prior to treatment, differences in abundancy and ligand expression in small clusters of immune cells as well as difference in baseline T-cell clonality drive response to checkpoint inhibition in aHCC. Citation Format: Sarah Cappuyns, Gino Philips, Vincent Vandecaveye, Chris Verslype, Eric Van Cutsem, Diether Lambrechts, Jeroen Derkervel. Pretreatment immune cell composition and checkpoint ligand expression define the response to immunotherapy in advanced HCC: a study using single-cell sequencing [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO002.
Abstract PO020: Identification of lipid species: potential biomarkers for early detection of hepatocellular carcinoma
Authors: Kit Yee Leung, KayLee Freitas, Yu Kuang
Journal: Clinical Cancer Research (2022)

Abstract Purpose of Study To investigate alterations in lipid metabolism during carcinogenesis from pretumor tissue towards hepatocellular carcinoma (HCC) and to identify lipid species biomarkers for early detection of HCC. Methods Liver tissue samples were collected from HCC patients. The samples were used to investigate the differences in lipid compositions between tumor and its surrounding hepatic tissue (SHT). A sample of the liver tumor and a sample of SHT were collected from each patient. A total of 32 samples were included in this study. Lipid profiling was performed using an automated electrospray ionization–tandem mass spectrometry with continuous infusion at 30 μl/min. The signal detection limit is 0.0005 mol. Concentrations of 1881 lipid species in tissue samples were analyzed. These lipid species include 348 species in 13 polar lipid groups, 44 species in triacylglycerol (TAG) group and 1489 species containing specific fatty acyl (FA). Lipid species with signal detected above or equal to the detection limit and coefficient of variation below 0.3 were retained for statistical analysis. Concentration differences in lipid species between HCC and SHT were compared using paired t-test or Wilcox signed rank. Differences in lipid compositions between HCC and SHT were assessed. Results Our study shows that significant difference (p &amp;lt; 0.05) of lipid species between SHT and HCC was found in 61 species including 50 species from polar lipid groups and 11 species from TAG group. Most of these species are phosphatidylcholine, ether-linked phosphatidylcholine and TAG species accounted for 36.07%, 13.11% and 18.03% respectively. In addition, significant changes in total ether-linked phosphatidylethanolamine (ePE) and total phosphatidylinositol (PI) were observed. Furthermore, there were significant decreases in FA 18:2 and FA18:3, but significant increase in FA 18:0 in HCC compared with that in SHT. Conclusions Our study suggests that total ePE, total PI, FA 18:0, FA 18:2 and FA 18:3 may serve as biomarkers for the early detection of HCC. Additional study is needed to understand the detailed mechanism of lipid alteration. Our study provides novel insights in the progress of pretumor tissue towards HCC. Citation Format: Kit Yee Leung, KayLee Freitas, Yu Kuang. Identification of lipid species: potential biomarkers for early detection of hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO020.
Abstract PO005: Obesity-associated Visfatin, and Silibinin in an <i>In Vitro</i> and <i>In Vivo</i> Model of Liver Cancer
Authors: Elisa Pedone, Kelly N Green, Kelly R Thornton, Ramona S. Price
Journal: Clinical Cancer Research (2022)

Abstract Introduction: Obesity, specifically body fatness, is a risk factor for the development of liver cancer. The link between obesity and liver cancer is likely to be mediated in part by a state of chronic inflammation. However, it has yet to be determined if visfatin inhibition, a pro-inflammatory adipocytokine upregulated by obesity, is sufficient to prevent or delay the progression of liver cancer. Obesity-induced inflammatory factors may promote cancer progression by increasing cell proliferation, motility, invasion, and metastasis.The use of dietary compounds may break the pro-inflammatory cycle induced by the obese state, thus attenuating the cancer process. Silibinin, a polyphenol in milk thistle seed, has been shown to have anti-inflammatory properties. Studies have yet to determine whether silibinin can be used to break the obesity-cancer link to delay progression of liver cancer. The objective of this cell culture and mouse study is to determine the efficacy of silibinin in the prevention of obesity-associated liver cancer progression. Methods: SNU-449 and HepG2 liver cancer cells were exposed to the following experimental conditions; control, FBS, visfatin (80 ng/ml), visfatin + silibinin 40 μM, silibinin (40 μM). Cell proliferation, lipogenesis, lactate dehydrogenase secretion, and ROS production were measured. Immunoblot was used to measure phospho-Akt, phospho-Erk, NF-kB, Bcl-xL, and actin. Eight-week-old C57BL/6J male mice were randomized to a high-fat DIO (n=6) or control diet (n=6). At 14 weeks, mice will be injected subcutaneously with syngeneic Hepa1-6 murine liver cancer cells. At 15-weeks, mice will receive peritoneal injections of silibinin 3 times per week for 2 weeks. Tumors will be measured and assessed for visfatin, Akt, Erk, and NF-kB protein expression. Results from the animal study are on-going and will be presented at time of the conference. Results: SNU-449 and HepG2 cells exposed to visfatin significantly increased cell proliferation and lipogenesis when compared to control. Further, the addition of silibinin inhibited the visfatin-induced proliferation and lipogenesis in both cell lines. Visfatin increased the phosphorylation of Akt and Erk, and NF-kB expression in both liver cancer cell lines. The addition of silibinin differently suppressed phosphorylation of Akt and Erk in SNU-449 and HepG2 cells. Conclusion: Silibinin differentially inhibits visfatin-induced cell growth, lipogenesis, and promotes cytotoxicity which may lead to increased cancer cell death. Citation Format: Elisa Pedone, Kelly N Green, Kelly R Thornton, Ramona S. Price. Obesity-associated Visfatin, and Silibinin in an In Vitro and In Vivo Model of Liver Cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO005.
Abstract IA28: Advances in the pathogenesis and classification of pediatric hepatocellular neoplasms
Authors: Dolores (Lola) Lopez-Terrada
Journal: Clinical Cancer Research (2022)

Abstract Hepatocellular neoplasms are the most common primary liver malignancies in children, with hepatoblastoma (HB) accounting for more than two-thirds of all cases. HB is a histologically heterogeneous embryonal tumor often recapitulating liver developmental stages, more commonly diagnosed during the first three years of life. HB classification has been historically challenged by its rarity and the lack of a systematic review of diagnostic tumor specimens. Recent international initiatives resulted in the development of international datasets (CHIC) and muti-consortia therapeutic trials (PHITT) that required a new pediatric liver tumors consensus classification. Meanwhile, genomic profiling is quickly advancing our understanding of HB and its biological heterogeneity, and allowing for the identification of biomarkers and biological subgroups of potential clinical relevance. Preliminary biological annotation of the International Consensus Classification, including diagnostic and prognostically relevant tumor subtypes, is ongoing. Molecular profiling of high-risk tumors, such as those in the HCN-NOS provisional category, is revealing histological and molecular features which are important to recognize to correctly diagnose and risk-stratify this group of patients. Current initiatives, including those led by clinical consortia participating in the International Pediatric Liver Tumors Trial (PHITT), are validating potential diagnostic and risk-stratifying biomarkers and engaged in exploratory studies, such genomic tumor profiling and investigation of novel therapeutic strategies, to be considered in upcoming trials. Citation Format: Dolores (Lola) Lopez-Terrada. Advances in the pathogenesis and classification of pediatric hepatocellular neoplasms [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA28.